Parkinson's Disease With Dementia Patients Research Articles

Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease

BackgroundCognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. ObjectiveTo investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. MethodsEighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. ResultsCompared with the control group, the macular GCIPL (t = −2.308, P = 0.023) was thinner and serum HMGB1 (z = −2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. ConclusionThe macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

Comparing the hippocampal volumetric atrophy between demented and nondemented individuals with Parkinson's disease: A systematic review and meta-analysis.

Parkinson's disease (PD) is one of the most common neurodegenerative conditions in the world and, when combined with dementia, can lead to immense cerebral volume loss. Of significant importance among all cerebral regions, is the hippocampus. This region plays a pivotal role in memory, and understanding its pathological alterations can answer vital questions regarding dementia. As such, we designed this study to compare the hippocampal volumes of PD patients with dementia (PDD) versus PD without dementia. PubMed, Web of Science, Scopus, and Embase were searched for relevant studies. We also searched the references sections of all included studies. The original search began in March 2022 and was extended to the end of July 2022. All related data were extracted from the studies. If the studies were conducted on patients from comparable patient groups, the most recent study with the most extensive data set would be included. A statistically significant difference was observed comparing the raw hippocampal volumes in participants with PDD and PD (p value = 0.01). In a comparison of normalized hippocampal volume between PDD and PD, there was a statistically significant difference (p value < 0.01), as well. Although further research is required to illuminate the temporal relation between the onset of dementia and hippocampal atrophy in demented PD individuals, the present study highlights the importance of utilizing volumetric studies on memory-related cerebral regions to diagnose the initiation of dementia in the early stages.

Gender differences in Parkinson's disease with dementia and dementia with Lewy bodies

BackgroundGender differences for dementia with Lewy bodies (DLB), usually considered an intermediate disease between Alzheimer disease (AD), Parkinson disease (PD), and Parkinson disease with dementia (PDD), is controversial. The present study investigated gender differences in DLB and PDD using demographic and pharmacologic treatment strategies in a retrospective data analysis. MethodData of confirmed cases of DLB and PDD between 2015 and 2020 were collected from the PRISMA dementia data-base registry. Data from 7594 PDD patients and 608 DLB patients were analyzed using logistic regression analysis to determine demographic and pharmacologic factors associated with DLB and PDD patients. ResultIn the adjusted analysis, central acetylcholinesterase inhibitors (ChEIs) including donepezil, galantamine, rivastigmine were associated with DLB. Second generation antipsychotics (SGAs) such as risperidone (odd ratio(OR)=1.900, 95% confidence interval (CI),1.192–3.030, P = 0.007) was associated with females with DLB while aripiprazole (OR=0.195,95% CI,0.06–0.631, P<0.006), and a selective serotonin receptor inhibitor (SSRIs) including escitalopram (OR=0.651, 95% CI,0.468–0.906, P = 0.011), and demographic factors including tobacco use (OR=0.620, 95% CI,0.444–0.866, P<0.005) and increasing age (OR =1.042, 95% CI, 1.025–1.058, P<0.001), were associated with females that present with PDD. Olanzapine (OR=2.871, 95% CI, 1.902–4.334, P<0.001), escitalopram (OR=1.444, 95% CI, 1.079–1.932) and tobacco use (OR=1.424, 95%CI, 1.075–1.887, P = 0.014) were associated with males with DLB. African American males (OR= 0.249, 95% CI, 0.088–0.703, P = 0.009) with a history of ethyl alcohol (ETOH) use (OR= 0.371, 95% CI, 0.260–0.531, P<0.001) treated with aripiprazole (OR=0.581, 95%CI, (0.302–1.118), P = 0.004) were associated with PDD. ConclusionOur findings reveal similarities and differences in demographic and pharmacologic factors associated with DLB and PDD. Investigating the effect of identified factors on DLB or PDD in future studies can help improve the care of DLB and PDD patients.

Correlation between serum 25(OH)D and cognitive impairment in Parkinson's disease

This study aimed to investigate the relationship between serum 25(OH)D and cognitive impairment in patients with Parkinson's disease (PD), hoping to provide possible ideas for the diagnosis and prevention of PD with cognitive impairment. Vitamin D is a neurosteroid with neurotrophic and neuroprotective functions, playing an important role in PD and its progression. In the present study, serum 25(OH)D levels were significantly decreased in PD patients (45.86 ± 14.81 nmol/L)compared to healthy controls(56.54 ± 14.00 nmol/L) (P < 0.001), and significant differences were also observed in PD patients with normal cognition (PD-NC), PD patients with mild cognitive impairment (PD-MCI)and PD patients with dementia (PDD)(P < 0.05). Moreover, there was a positive correlation between serum 25(OH)D levels and Montreal cognitive assessment(MoCA) scores (r = 0.489,P < 0.001).The increased serum 25(OH)D was an independent protective factor of cognitive impairment in PD (OR = 0. 949, P = 0.005), and the sensitivity, specificity, and AUC under the ROC curve area of serum 25(OH)D were 53.3%, 86.5%, and 0.713, respectively. These findings support the relationship between cognitive impairment and Vitamin D in PD patients. Serum 25(OH)D may be a useful biomarker for diagnosing cognitive impairment in patients with PD.

Neural correlates of working memory and compensation at different stages of cognitive impairment in Parkinson’s disease

Working memory (WM) impairment is one of the most frequent cognitive deficits in Parkinson's disease (PD). However, it is not known how neural activity is altered and compensatory responses eventually fail during progression. We aimed to elucidate neural correlates of WM and compensatory mechanisms in PD. Eighteen cognitively normal PD patients (PD-CogNL), 16 with PD with mild cognitive impairment (PD-MCI), 11 with PD with dementia (PDD), and 17 healthy controls (HCs) were evaluated. Subjects performed an n-back task. Functional MRI data were analyzed by event-related analysis for correct responses. Brain activations were evaluated by comparing them to fixation cross or 0-back task, and correlated with n-back task performance. When compared to fixation cross, PD-CogNL patients had more activation in WM areas than HCs for both the 2- and 3-back tasks. PD-MCI and PDD patients had more activation in WM areas than HCs for the 0- and 1-back task. 2-back task performance was correlated with brain activations (vs. 0-back task) in the bilateral dorsolateral prefrontal cortex and frontal eye field (FEF) and left rostral prefrontal cortex, caudate nucleus, inferior/superior parietal lobule (IPL/SPL), and anterior insular cortex as well as anterior cingulate cortex. 3-back task performance was correlated with brain activations (vs. 0-back task) in the left FEF, right caudate nucleus, and bilateral IPL/SPL. Additional activations on top of the 0-back task, rather than fixation cross, are the neural correlates of WM. Our results suggest PD patients have two types of compensatory mechanisms: (1) Hyperactivation for different WM load tasks depending on their cognitive status. PD-CogNL have hyperactivation for moderate and heavy working memory load tasks while maintaining normal working memory performance. In contrast, PD-MCI and PDD have hyperactivation for control task and light working memory load task, leaving less neural resources to further activate for more demanding tasks and resulting in impaired working memory performance. (2) Bilateral recruitment of WM-related areas, in particular the DLPFC, FEF, IPL/SPL and caudate nucleus, to improve WM performance.

The influence of white matter hyperintensity on cognitive impairment in Parkinson's disease.

The aim of this meta‐analysis was to review systematically and to identify the relationship between the severity and location of white matter hyperintensities (WMHs) and the degree of cognitive decline in patients with Parkinson’s disease (PD). We searched the PubMed, EMBASE, Web of Science, Ovid, and Cochrane Library databases for clinical trials of the severity and location of WMHs on the degree of cognitive impairment in PD through October 2020. We conducted the survey to compare the association of WMH burden in patients with PD with mild cognitive impairment (PD‐MCI) versus those with normal cognition (PD‐NC) and in patients with PD with dementia (PDD) versus those with PD without dementia (PD‐ND). Nine studies with PD‐MCI versus PD‐NC and 10 studies with PDD versus PD‐ND comparisons were included. The WMH burden in PD‐MCI patients was significantly different compared to that in PD‐NC patients (standard mean difference, SMD = 0.39, 95% CI: 0.12 to 0.66, p = 0.005), while there was no correlation shown in the age‐matched subgroup of the comparison. In addition, PDD patients had a significantly higher burden of WMHs (SMD = 0.8, 95% CI: 0.44 to 1.71, p < 0.0001), especially deep white matter hyperintensities (SMD = 0.54, 95% CI: 0.36 to 0.73, p < 0.00001) and periventricular hyperintensities (SMD = 0.70, 95% CI: 0.36 to 1.04, p < 0.0001), than PD‐NC patients, regardless of the adjustment of age. WMHs might be imaging markers for cognitive impairment in PDD but not in PD‐MCI, regardless of age, vascular risk factors, or race. Further prospective studies are needed to validate the conclusions.

Exploring Bottom-Up Visual Processing and Visual Hallucinations in Parkinson's Disease With Dementia.

Visual hallucinations (VH) are a common symptom of Parkinson's disease with dementia (PDD), affecting up to 65% of cases. Integrative models of their etiology posit that a decline in executive control of the visuo-perceptual system is a primary mechanism of VH generation. The role of bottom-up processing in the manifestation of VH in this condition is still not clear although visual evoked potential (VEP) differences have been associated with VH at an earlier stage of PD. Here we compared the amplitude and latency pattern reversal VEPs in healthy controls (n = 21) and PDD patients (n = 34) with a range of VH severities. PDD patients showed increased N2 latency relative to controls, but no significant differences in VEP measures were found for patients reporting complex VH (CVH) (n = 17) compared to those without VH. Our VEP findings support previous reports of declining visual system physiology in PDD and some evidence of visual system differences between patients with and without VH. However, we did not replicate previous findings of a major relationship between the integrity of the visual pathway and VH.

Association of the serum microRNA-29 family with cognitive impairment in Parkinson's disease.

We aimed to examine whether miRNA-29s (miR-29s) in serum are associated with cognitive impairment in Parkinson’s disease (PD). Thirty-nine PD patients with normal cognition (PD-NC), 37 PD patients with mild cognitive impairment (PD-MCI), 22 PD patients with dementia (PDD) and 40 healthy controls were recruited. Detailed clinical evaluations and a schedule of neuropsychological tests were administered to all patients. MiR-29s expression in serum samples was assessed using reverse-transcription quantitative real-time PCR. We found that the levels of all three miR-29s in the PDD group were significantly lower than those in the PD-NC group (p < 0.05). In addition, the miR-29b level was downregulated in the PD-MCI group with respect to that in the PD-NC group (p < 0.05). After adjusting for years of education and the UPDRS-III subscore using a multivariate model, miR-29s showed significant associations with PDD. MiR-29b levels were shown to be associated with different subsets of PD cognition and could accurately discriminate PDD from non-PDD (area under the curve (AUC) = 0.859; 95% CI, 0.7817-0.9372). Further analysis of the cognitive domains found that the miR-29s levels were all associated with memory performance in PD patients. In summary, miR-29s are associated with cognitive impairment in PD.

Depression and financial capacity assessment in Parkinson's disease with dementia: Overlooking an important factor?

Depression affects cognitive abilities, such as thinking, concentration and making decisions in both young adults and elders. However, financial capacity (which consists of multiple cognitive domains and specific skills) and depression in Parkinson's disease with dementia (PDD) are little investigated. Sixty participants divided into four groups (PDD with and without depressive symptoms, non-demented elders with and without depression) were examined with the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS-15) and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) - full and short form. Results indicated that PDD patients' performance in cognitive functioning and financial capacity is severely impaired, while there is a statistically significant difference between depressed and non-depressed PDD patients. Differences in financial capacity performance indicate that depression should not be disregarded. Further studies on larger PDD population are necessary in order to investigate the decisive role of depression on financial capacity impairment.

Clinical characteristics of cognitive impairment in patients with Parkinson's disease and its related pattern in 18 F-FDG PET imaging.

This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo-parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD.

Brain degeneration in Parkinson's disease patients with cognitive decline: a coordinate-based meta-analysis.

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disease, with its severity increasing as the neurodegenerative process advances. The present meta-analysis used anisotropic effect size seed-based d mapping software to perform analyses using both functional and structural brain imaging data. The analyses were between PD patients with mild cognitive impairment (PD-MCI) and PD patients with dementia (PDD) compared to PD cognitively unimpaired patients (PD-CU) and PD patients without dementia (PD-ND) respectively. Thirty-four studies were found and split into three analyses: 405 PD-MCI patients compared to 559 PD-CU patients from 1) 15 studies with structural imaging modalities and 2) eight studies with functional imaging modalities, as well as 178 PDD patients compared to 278 PD-ND patients (which includes both PD-CU and PD-MCI) in 3) 11 studies with structural imaging modalities. Statistical threshold was set to uncorrected p < 0.001. We found several brain regions that differed between PD-MCI and PD-CU patients: the left insula, bilateral dorsolateral prefrontal cortex, left angular gyrus, midcingulate cortex, and right supramarginal gyrus. The brain regions identified in the PD-MCI analyses are associated with the somatosensory network and executive processing. In PDD patients, the bilateral insula and right hippocampus were found as regions of structural atrophy. The insula was found in both structural analyses of PD-MCI and PDD, with unilateral insula involvement in PD-MCI extending to bilateral insula involvement in PDD. The results found both a spectrum of increasing brain atrophy in PD cognitive impairment and supports the existence of sub-typing in PD-MCI.

White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease

BackgroundIn dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. MethodsWe retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. ResultsWMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. ConclusionOur results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

Utility of Autonomic Function Tests to Differentiate Dementia with Lewy Bodies and Parkinson Disease with Dementia from Alzheimer Disease

Objective: We studied autonomic disturbance in patients with dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD), Alzheimer disease (AD), to determine whether autonomic function tests can be used to distinguish these disorders. Methods: Autonomic function was tested in 56 patients with DLB, 37 patients with PDD, and 59 patients with AD by using the sympathetic skin response, coefficient of variation in R-R interval, the head-up tilt test, serum norepinephrine concentration, and 123I-meta-iodobenzylguanidine cardiac scintigraphy. Symptoms of autonomic dysfunction, such as constipation, urinary symptoms, and orthostatic hypotension, were also noted. Results: The groups did not differ on baseline characteristics other than those associated with Parkinsonism and dementia. All patients with DLB and PDD had some dysautonomia, whereas rates were much lower for patients with AD (19%). Significantly more DLB and PDD patients than AD patients showed abnormalities on autonomic function tests. Conclusions: Autonomic function tests might be quite useful to distinguish DLB and PDD from AD.

Transcranial Sonographic Alterations of Substantia Nigra and Third Ventricle in Parkinson's Disease with or without Dementia.

Background:Numerous studies have demonstrated that patients with Parkinson's disease (PD) have a higher prevalence of substantia nigra (SN) hyperechogenicity compared with controls. Our aim was to explore the neuroimaging characteristics of transcranial sonography (TCS) of patients with PD and those with PD with dementia (PDD). The correlation between the echogenicity of the SN and clinical symptoms in Chinese patients with PDD was also assessed.Methods:The ratios of SN hyperechogenicity (SN+), maximum sizes of SN+, and widths of third ventricle (TV) were measured using TCS for all the recruited patients. Data were analyzed using one-way analysis of variance, rank-sum test, Chi-square test, and receiver-operating characteristic (ROC) curve analysis.Results:The final statistical analysis included 46 PDD patients, 52 PD patients, and 40 controls. There were no significant differences in ratios of SN+ and maximum sizes of SN+ between PDD and PD groups (P > 0.05). TV widths were significantly larger in PDD group (7.1 ± 1.9 mm) than in PD group (6.0 ± 2.0 mm) and controls (5.9 ± 1.5 mm, P < 0.05); however, the ratios of enlarged TV did not differ among the three groups (P = 0.059). When cutoff value was set at 6.8 mm, the TV width had a relatively high sensitivity and specificity in discriminating between PDD and PD groups (P = 0.030) and between PDD group and controls (P = 0.003), based on ROC curve analysis. In PDD patients, SN+ was more frequently detected in akinetic-rigid subgroup, and patients with SN+ showed significantly higher Hoehn and Yahr stage and Nonmotor Symptoms Questionnaire scores (P < 0.05).Conclusions:Compared to Chinese patients with PD, patients with PDD had a wider TV, altered SN sonographic features, and more severe clinical symptoms. Our findings suggest that TCS can be used to assess brain atrophy in PD and may be useful in discriminating between PD with and without dementia.

Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias.

The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical β-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD. Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future α-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers Across the Spectrum of Lewy Body Diseases: Results from a Large Multicenter Cohort.

Concomitant Alzheimer's disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). We included 375 DLB patients, 164 Parkinson's disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

Distribution and Load of Amyloid-β Pathology in Parkinson Disease and Dementia with Lewy Bodies.

Parkinson disease (PD), Parkinson disease with dementia (PDD), and Dementia with Lewy bodies (DLB) differ clinically with regard to the presence and timing of dementia. In this postmortem study, we evaluated whether the burden and distribution pattern of amyloid-β (Aβ) pathology differs among these disease entities. We assessed Aβ phases and neuritic plaque scores in 133 patients fulfilling clinical diagnostic criteria for PD, PDD, and DLB, and determined the presence and load of Aβ pathology in 5 cortical and 4 subcortical regions in a subset of patients (n = 89) using a multispectral imaging system. Aβ phases and neuritic plaque scores were higher in DLB versus PDD (both p < 0.001) and in PDD vs PD patients (p = 0.020 and 0.022, respectively). Aβ pathology was more often observed in the entorhinal cortex, amygdala and putamen in DLB versus PDD patients; Aβ load was higher in both cortical and subcortical regions. PDD patients had more frequent Aβ pathology in temporal cortex and higher Aβ load in cortical regions and striatum versus PD patients. Our findings suggest that the load and extent of Aβ pathology may contribute to cognitive dysfunction in PDD and the early-stage severe dementia in DLB.

Voxel-based meta-analysis of gray matter volume reductions associated with cognitive impairment in Parkinson's disease.

Brain gray matter volume (GMV) reduction has been reported in Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) and in PD patients with dementia (PDD) with cumulative evidence using voxel-based morphometry (VBM). However, the findings of these studies have not been entirely concordant. Whole-brain VBM studies comparing PD-MCI with PD patients without cognitive impairment (PD-NCI) and comparing PDD with PD patients without dementia (PDND) were systematically searched in PubMed and EMBASE databases from January 1995 to December 2015. Coordinates with significant differences were extracted from each cluster. Meta-analysis was performed using AES-SDM to quantitatively evaluate the GMV changes. Five studies comparing 92 PD-MCI with 192 PD-NCI patients were included in the PD-MCI vs. PD-NCI meta-analysis. Ten studies with 168 PDD and 233 PDND patients were included in the PDD vs. PDND meta-analysis. Compared with PD-NCI, GMV reductions were observed in left superior temporal lobe, left insula and left superior frontal lobe in PD-MCI patients. Significant GMV reduction were found in bilateral superior temporal lobe extending to hippocampus, and left superior frontal lobe in PDD patients comparing with PDND. Meta-regression of PDD studies showed that disease duration was negatively correlated with GMV in the left superior frontal lobe. GMV reductions in the frontal-limbic-temporal regions were main features of cognitive decline in PD. Unilateral-to-bilateral development of GMV reduction in the frontal-limbic-temporal regions is a possible indicator for PD-MCI to PDD progression, whereas significant hippocampal GMV reduction may not be a marker for early cognitive decline in PD.

An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia.

Biomarkers from multiple modalities have been shown to correlate with cognition in Parkinson’s disease (PD) and in Alzheimer’s disease (AD). However, the relationships of these markers with each other, and the use of multiple markers in concert to predict an outcome of interest, are areas that are much less explored. Our objectives in this study were (1) to evaluate relationships among 17 biomarkers previously reported to associate with cognition in PD or AD and (2) to test performance of a five-biomarker classifier trained to recognize AD in identifying PD with dementia (PDD). To do this, we evaluated a cross-sectional cohort of PD patients (n = 75) across a spectrum of cognitive abilities. All PD participants had 17 baseline biomarkers from clinical, genetic, biochemical, and imaging modalities measured, and correlations among biomarkers were assessed by Spearman’s rho and by hierarchical clustering. We found that internal correlation among all 17 candidate biomarkers was modest, showing a maximum pairwise correlation coefficient of 0.51. However, a five-marker subset panel derived from AD (CSF total tau, CSF phosphorylated tau, CSF amyloid beta 42, APOE genotype, and SPARE-AD imaging score) discriminated cognitively normal PD patients vs. PDD patients with 80% accuracy, when employed in a classifier originally trained to recognize AD. Thus, an AD-derived biomarker signature may identify PDD patients with moderately high accuracy, suggesting mechanisms shared with AD in some PDD patients. Based on five measures readily obtained during life, this AD-derived signature may prove useful in identifying PDD patients most likely to respond to AD-based crossover therapies.

Structural and functional imaging study in dementia with Lewy bodies and Parkinson's disease dementia.

Dementia with Lewy Bodies (DLB) and Parkinson's disease with Dementia (PDD) are neurodegenerative disorders with complex clinical picture (parkinsonism, cognitive decline and neuropsychiatric disturbances). The conundrum of whether DLB and PDD represent the same or different entities is still under debate. Advanced neuroimaging techniques may represent a point of view to assess brain correlates in DLB and PDD. The study aimed at evaluating whether DLB and PDD may be labelled under the same disease entity or be considered distinctive pathologies. We compared DLB and PDD patients by assessing structural and functional brain imaging and including PD patients. Patients with diagnosis of PD, PDD, DLB and a group of healthy controls for neuroimaging comparisons were recruited and changes in structural and resting-state functional MR (Regional Homogeneity, ReHo) were studied. No significant atrophy in VBM analysis was evident in PD. Conversely, PDD showed a significant bilateral frontal atrophy, whereas DLB was characterized by a predominant parietal, occipital atrophy; a similar involvement of subcortical regions in PDD and DLB was observed. ReHo demonstrated reduced local coherence of frontal regions in PD and in PDD, whereas DLB patients presented a reduced local connectivity in posterior regions. Different brain areas are specifically involved in PDD and DLB. In the former group, greater atrophy of frontal regions with concomitant functional connectivity impairment was evident; conversely, structural and functional damage in the posterior regions characterized DLB. Despite an overlapping clinical spectrum, DLB and PDD have different networks involved and different underlying pathogenic pathways.